The blood-brain barrier (BBB) is a highly regulated dynamic interface that separates the peripheral circulating blood supply from the central nervous system. Many acute and chronic neurodegenerative diseases show regional degenerative changes and modified BBB integrity. Migraine is a common and potentially debilitating neurological disorder characterized by a paroxysmal unilateral throbbing pain and is often associated with aura, nausea, vomiting, and photophobia. Triptans (serotonin IB/ID receptor agonists) are often used migraine therapy and are thought to relieve headache pain, in part, by inhibiting the release of pronociceptive transmitters through actions on 5HT1B/1D receptors on trigeminal afferent neurons. However, frequent use of triptans over an extended period increased the frequency of migraines in migraineurs, a condition termed medication overuse headache (MOH). Since migraineurs are the most susceptible to develop MOH, some common neuronal mechanisms between migraine and MOH may be expected. The mechanisms that underlie medication overuse headache are not fully understood. Evidence suggests that changes in BBB integrity may play a key role in several clinical situations in which migraine headache is a major feature. We suggest that prolonged exposure to triptans or medication withdrawal results in BBB dysfunction, increasing the potential for the induction of headache. To test this hypothesis, we will use neurochemical, and pharmacological strategies in a rat model of triptan-induced latent sensitization to determine potential structural and functional changes in BBB integrity in two pain pathway brain regions. Medication withdrawal will be precipitated with 5-HT1B/1D antagonist (GRI27935). Behavioral cutaneous allyodyna responses will be assessed and correlated to changes in BBB integrity. Establishing the mechanisms that underlie the pathobiology of MOH will assist in the development of new therapeutic strategies for the treatment of migraine and MOH.